Substituted nitrosalicylanilides

ABSTRACT

WHEREIN R is hydrogen or methyl. These compounds are found to be particularly useful as bacteriostats, as lamprecides and as differential fish toxicants. The compounds are found to be particularly effective for such purposes because of the nitro group in the 5&#39;&#39; position and because of the tertiary-butyl group in the 3 position.   The compounds disclosed herein are defined by the formula

United States Patent Meek [451 May 30, 1972 54 sUBsT Tur DNITROSALVICYLANILIDES [72] Inventor: William H. Meek, Northfield, Ohio[73] Assignee: Ferro Corporation, Cleveland, Ohio [22] Filed: Feb. 9,1970 [21] App]. No.: 9,981

[52] US. Cl. ..260/559 S, 424/324 [51] Int. Cl ..C07c 103/26 [58] Fieldof Search ..260/559 S [56] References Cited UNITED STATES PATENTS3,079,297 2/1963 Schraufstatter et a1 ..260/559 S 3,147,300 9/1964Schraufstatter et al... ....260/559 S 3,375,160 3/1968 Early et a1..260/559 S Primary ExaminerHenry R. Jiles Assistant Examiner-S. D.Winters Att0rney--Milt0n L. Simmons [57] ABSTRACT The compoundsdisclosed herein are defined by the formula OH R (CH;)5C-321 CONH 4 a6'4 5 R All N 02 wherein R is hydrogen or methyl. These compounds arefound to be particularly useful as bacteriostats, as lamprecides and asdifferential fish toxicants. The compounds are found to be particularlyeffective for such purposes because of the nitro group in the 5 positionand because of the tertiarybutyl group in the 3 position.

5 Claims, No Drawings SUBSTIUJTEP,NITBOSALICXLANLLIDES BACKGROUND OF THEINVENTION 1. Field of the Invention The present invention relates tosubstituted nitrosalicylanilides. More specifically, it relates tosubstituted nitrosalicylanilides having a nitro group in the positionand a tertiary-butyl group in the 3 position, preferably with a methylradical in the 2 position.

2. Description of the Related Prior Art A number of substitutednitrosalicylanilides are disclosed in the prior art. For example,Schraufstatter et a] U. S. Pat. Nos. 3,029,297 and 3,147,300 disclose anumber of nitrosalicylanilides in which the nitro groups are in the 2and 4' positions and also have chlorine in the 5 position, and in somecases chlorine in the 2 position. These compounds are described as beingvery active gastropodicidal agents. In such compounds, the nitro groupsare in the 4' position or 2 position.

SUMMARY OF THE INVENTION In accordance with the present invention, ithas now been found that nitrosalicylanilides having a nitro group in the5 position and a tertiary-butyl radical in the 3 position, together withchlorine in the 5 position and methyl or hydrogen in the 2 and 4positions, give compounds which are very effective as bacteriostats,lamprecides and differential fish toxicants. These new compounds arefound to be much more effective for such purposes than correspondingcompounds which have the nitro group in the 4 position or a positionother than the 5' position and which do not have the tertiary-butylgroup. The compounds of this invention can be represented by the formulaOH R 1 N02 wherein R is methyl or hydrogen.

When there is no substituent group in the 2' position, the nitro groupcan be referred to as either in the 5 or 3 position. However, sincenomenclature rules require use of the lowest possible number, this isreferred to as the 3 nitro instead of the 5 nitro derivative. While itis preferred to have the methyl substituent group in the 2 position, itis also effective to have methyl in the 4 position or in both the 2 andthe 4' positions.

The compounds of this invention can be prepared by reacting3-tertiary-butyl-S-chloro-salicylic acid with metanitroaniline, or asubstituted derivative thereof having a methyl radical in the 6 and/or 4position. These derivatives can also be referred to as2-methyl-5-nitroaniline or 4-methyl- S-nitroaniline, etc. The reactionis advantageously conducted in the presence of a dehydrating agent andin the presence of an inert solvent, such as chlorobenzene andtetrachloroethane.

At temperatures of 60 C. to about 150 C., the reaction is completed in 1to 8 hours, the reaction proceeding more quickly at the highertemperatures. Dehydrating agents are preferably used, such as PCl andSOCI These compounds can also be prepared by reacting the ap propriatesubstituted salicyloyl chloride with meta nitroaniline or appropriatederivative. The temperature advantageously is 5-60 C. and reaction issubstantially completed in 1% to 3 hours.

This reaction is also advantageously conducted in an inert solvent suchas chlorobenzene, tetrachloroethane, pyridine and N,N-dimethylamides,e.g., dimethylformamide, dimethylacetamide and dimethylpropionamide.

Where the preparation is effected in solution, the product is recoveredby precipitation and filtration. The product can be precipitated fromthe reaction medium by the addition of methyl alcohol.

Typical compounds of this invention include:

3-tert.butyl-5-chloro-2'-methyl-5-nitrosalicylanilide 73-tert.butyl-5-chloro-3 nitrosalicylanilide3-tert.butyl-S-chloro-4-methyl-5'-nitrosalicylanilide3-tert.butyl-5-chloro-2,4'-dimethyl-5 '-nitrosalicylanilide.

The compounds of this invention are particularly useful as lamprecides.These compounds are particularly effective in that the compounds areunharmful to trout when used in amounts as high as 4 times that foundsufficient to kill the lamprey larva.

These compounds are also found to be toxic to less desirable fish suchas carp, and non-toxic to more desirable fish such as blue gill in dosesthat are sufficient to kill the carp. In evaluating differential fishtoxicity, the test is similar to that used in the lamprey tests, exceptthat each test is conducted with 10 specimens of the individual species,and the tests are conducted in fresh water at about 12 C.

In conducting bacteriostat tests, the following procedure is used: thetest compounds are dissolved in a suitable solvent (typicallydimethylforrnamide) and incorporated in nutrient agar (for bacteria) orSabouraud agar (for fungi) at various concentrations. The plates arethen streaked with cultures of various bacteria or fungi. Afterincubation for 48 hours at 37 C. (for bacteria) or for one week at 25 C.(for fungi), the plates are examined for evidence of growth of theseorganisms. The minimum concentration necessary for complete inhibitionof growth is recorded.

The organisms tested are:

Staphylococcus aureus, a Gram-positive bacterium common on the humanskin, and responsible for certain infections and for objectionableodor-forming reactions;

Escherichia call and Pseudomonas aeruginosa, two Gramnegative bacteriacapable of causing serious secondary and occasionally primaryinfections; and

Aspergillus Niger and Penicillium citrinum, two fungi typical of formswhich grow on foods, and on some synthetic surface coatings.

All are either economically important per se, or are used asexperimental indicators of the growth pattern of related more dangerousorganisms.

The lamprey test used herein is essentially that described in circular185 of the Bureau of Sports Fisheries and Wildlife, U. S. Department ofthe Interior (1964). In these tests Lake Huron water is used, and a testperiod of 24 hours and a water I temperature of'55 F. are also used. Ineach case two lampreys and two rainbow trout are used.

The optimum concentrations for the use of the compounds of thisinvention will vary somewhat according to the temperature, pH, etc. Forcontrolling lamprey the effective concentration is advantageously in therange of 0.03 to 1 part per million. The compound is added in liquidform as a solution, suspension or emulsion. Such procedures are alsodiscussed in U.S. Pat. No. 2,821,499. The concentration of toxicant foractual use will vary depending upon temperature, pH of the water, typesof food and game fish. Optimum concentrations are preferably determinedexperimentally by laboratory tests simulating conditions of contemplateduse.

The invention is illustrated by the following examples. These examplesare given merely for illustrative purposes and are not intended to limitthe scope of the invention nor the manner in which it may be practiced.Unless indicated otherwise, pans and percentages are given by weight.

EXAMPLE I 3-t-Butyl-5-chloro-2-methy1-5 -nitrosalicylanilide To a 500milliliter reaction flask equipped with stirrer, thermometer, condenserand drying tube positioned at the top of the condenser, there is added68.7 grams of 3-t-butyl-5- chloro-salicylic acid, 49.4 grams of2-methyl-5-nitroaniline, 13.8 grams of PC];, and 400 ml. ofchlorobenzene. The resultant mixture is heated at reflux temperature for2 hours. Then the hot solution is filtered and allowed to cool to roomtemperature. The precipitate is recovered by filtration andrecrystallized from chlorobenzene to give 3-t-butyl-5-chloro-2'-methyl-5'-nitrosalicylanilide in a 50 percent yield with a meltingpoint of 4 C.

EXAMPLE I] 3-t-Butyl-5-chloro-3 -nitrosalicylanilide The procedure ofExample I is repeated using an equivalent amount of meta-nitroaniline inplace of the substituted nitroaniline of Example I, and 45.6 grams (43.6percent theoretical) of the desired product are obtained with a meltingpoint of l 58-160 C.

EXAMPLE III The procedure of Example I is repeated twice using in onecase an equivalent amount of 4-methyl-3-nitroaniline and in the othercase an equivalent amount of 2,4-dimethyl-3- nitroaniline in place ofthe substituted nitroaniline of Example I to give3-t-butyl-5-chloro-4-methyl-3'-nitroaniline and3-tbutyl-S-chloro-2,4-dimethyl-5 -nitroaniline.

EXAMPLE IV A number of tests are carried out in IO-liter glass jars inchdiameter) each containing 6 liters of test solution. The jars areaerated by means of standard stone air breakers to maintain oxygenlevels at near saturation. The temperature is maintained constant at 55F. by immersion of the test jars in a water bath maintained at thattemperature. The test animals range from about 3 to 5 inches in lengthand comprise larvae of the sea lamprey (Pelromyzon marinus) andfingerline rainbow trout (Salmo gaira'neri). The animals are allowed tobecome acclimated to the temperature of the test solution, and thenappropriate amounts of the toxicant, dissolved in a solvent such asdimethylforrnamide, are added to produce the desired concentrations. Thefollowing Table I shows the results of tests using the compounds ofExample I and II and the excellent results produced thereby.

TABLE I 3-t-Butyl-5-chloro-2 '-methyl-5 '-nitrosalicylanilide LampreysRainbow Trout Concentration in parts per Number Mortality NumberMortality million of test (percent of of test (percent of animals totaltest animals total test animals) animals) 0.3 2 100% 2 0% 0.] 2 100% 20% 0.07 2 100% 2 0% It can be seen from the above data that thecompounds are not only selective toward lamprey larva, but are unusuallyeffective at very minor amounts.

EXAMPLE V TABLE II Name of Compound TIL 5 3-t-Butyl-5-chloro-2-methyl-5-nitrosalicylanilide 3-t-Butyl-5-chloro-3 -nitrosalicylanilide3-t-Butyl-5-chloro-4-nitrosalicylanilide S-chloro-El-nitrosalicylaniliderr w OLA The last compound has no t-butyl group, and the results showthat the presence of the t-butyl group increases the T/L ration from 1.0to 3.

EXAMPLE VI EXAMPLE VH The same compounds used in Example VI are testedas differential fish toxicants using the conditions described above forthis purpose and running the tests for 96 hours. The 5- nitro compoundof Example I is found much superior compared to its counterpart in whichthe nitro group is present in the 4' position. The compound of Example Ikills all carp at a concentration of 0.1 ppm and at the sameconcentration will kill no blue gill in the 96 hour test period. Incontrast, while the counterpart compound having the nitro group in the 4position kills all carp at 0.1 ppm, at the same time it kills 10 percentof the blue gill.

Similar effective results are obtained when the compounds of Example IIIare used in the tests of Examples IV, VI and VII.

While certain features of this invention have been described in detailwith respect to various embodiments thereof, it will, of course, beapparent that other modifications can be made within the spirit andscope of this invention and it is not intended to limit the invention tothe exact details shown above except insofar as they are defined in thefollowing claims: The invention claimed is:

l. A compound having the formula OH R (CHa)sC OONH R all I110:

wherein R is H or CH 2. The compound of claim 1 comprising3-tertiary-butyl-5- chloro-2-methyl-5'-nitrosalicylanilide.

3. The compound of claim 1 comprising S-tertiary-butyLS- chloro-3'-nitrosalicylanilide. 6O 4. The compound of claim 1 comprising3-tertiary-butyl-5- chloro-2,4'-dimethyl-5-nitrosalicylanilide.

5. The compound of claim 1 comprising 3-tertiary-butyl-5-chloro-4'-methyl-5-nitrosalicylanilide.

2. The compound of claim 1 comprising3-tertiary-butyl-5-chloro-2''-methyl-5''-nitrosalicylanilide.
 3. Thecompound of claim 1 comprising3-tertiary-butyl-5-chloro-3''-nitrosalicylanilide.
 4. The compound ofclaim 1 comprising3-tertiary-butyl-5-chloro-2'',4''-dimethyl-5''-nitrosalicylanilide. 5.The compound of claim 1 comprising3-tertiary-butyl-5-chloro-4''-methyl-5''-nitrosalicylanilide.